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ACUTE MYELOID LEUKEMIA

In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2

Leukemia volume 36, pages 1313–1323 (2022)Cite this article

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Abstract

Treatment options for patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are scarce. Recurring mutations, such as mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2) are found in subsets of AML and MDS, are therapeutically targeted by mutant enzyme-specific small molecule inhibitors (IDHmi). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDHmi alone are not curative and resistance commonly develops, underscoring the importance of alternate therapeutic options. We were first to report that IDH1/2 mutations induce a homologous recombination (HR) defect, which confers sensitivity to poly (ADP)-ribose polymerase inhibitors (PARPi). Here, we show that the PARPi olaparib is effective against primary patient-derived IDH1/2-mutant AML/ MDS xeno-grafts (PDXs). Olaparib efficiently reduced overall engraftment and leukemia-initiating cell frequency as evident in serial transplantation assays in IDH1/2-mutant but not -wildtype AML/MDS PDXs. Importantly, we show that olaparib is effective in both IDHmi-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDHmi. Our pre-clinical studies provide a strong rationale for the translation of PARP inhibition to patients with IDH1/2-mutant AML/ MDS, providing an additional line of therapy for patients who do not respond to or relapse after targeted mutant IDH inhibition.

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Fig. 1: Olaparib targets IDH2-mutant AML blasts and leukemia initiating cells in vivo.
Fig. 2: Enasidenib resistant AML is sensitive to olaparib administration both in vitro and in vivo.
Fig. 3: Olaparib remains effective in a second enasidenib-resistant IDH2-mutant AML PDX.
Fig. 4: PARP inhibition is also effective in IDH1-mutant AML and IDH1/2-mutant MDS.

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All relevant data are available from the authors upon reasonable request.

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Acknowledgements

We thank Yale Pathology Tissue Services especially A. Brooks for research histology services. We thank Yale Animal Resources Center, especially P. Ranney, J. Fonck for animal care. We thank Yale Flow Cytometry Core, especially Lesley Devine, Diane Trotta and Chao Wang for flow cytometry analysis. We thank our patients for donating blood and bone marrow to research. This study was supported in part by the NIH/NIDDK R01DK102792 (to S.H.), The Frederick A. Deluca Foundation and the Vera and Joseph Dresner Foundation (to S.H.), the Howard Hughes Medical Institute (to R.A.F), the General Program of the National Natural Science Foundation of China (Grant No.82170137, to Y.S.), and the Leukemia and Lymphoma Society and the NIH/NCI R01CA266604 (to S.H. and R.S.B.). X.F. was supported by the Young Scientists Fund of the National Natural Science Foundation of China (Grant No. 81801588). Y.G. was supported by the American Society of Hematology Scholar Award. T.T. was supported by AIRC under MFAG 2020 (project ID. 24883). This study was supported by the Animal Modeling Core and the Pilot and Feasibility Program of the Yale Cooperative Center of Excellence in Hematology (NIDDK U54DK106857).

Author information

Author notes

  1. Yuanbin Song

    Present address: Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510062, China

  2. These authors contributed equally: Rana Gbyli, Yuanbin Song, Wei Liu, Yimeng Gao.

Authors and Affiliations

  1. Section of Hematology, Department of Internal Medicine and Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, 06520, USA

    Rana Gbyli, Yuanbin Song, Wei Liu, Yimeng Gao, Giulia Biancon, Namrata S. Chandhok, Xiaman Wang, Xiaoying Fu, Amisha Patel, Toma Tebaldi, Padmavathi Mamillapalli, Amer M. Zeidan, Thomas Prebet & Stephanie Halene

  2. Section of Hematology, Department of Internal Medicine, University of Miami, Sylvester Comprehensive Cancer Center, Miami, FL, USA

    Namrata S. Chandhok

  3. Department of Hematology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, P. R. of China

    Xiaman Wang

  4. Department of Laboratory Medicine, Shenzhen Children’s Hospital, Shenzhen, P. R. of China

    Xiaoying Fu

  5. Department of Therapeutic Radiology, Yale University, New Haven, CT, 06520, USA

    Ranjini Sundaram & Ranjit S. Bindra

  6. Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, 38121, Italy

    Toma Tebaldi

  7. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA

    Richard A. Flavell

  8. Howard Hughes Medical Institute, Yale University, New Haven, Connecticut, USA

    Richard A. Flavell

  9. Department of Pathology, Yale University, New Haven, CT, 06520, USA

    Ranjit S. Bindra & Stephanie Halene

  10. Yale Stem Cell Center and Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

    Stephanie Halene

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  1. Rana Gbyli
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Contributions

Conceptualization: SH, RSB, and YS; Methodology: SH, RG, and YS; Investigation: YS, RG, WL, YG, GB, XW, XF, NC, RS, AP, TT, and PM; Data analysis: YS, RG, and SH; Validation: YS, RG, and SH; Writing—original draft: SH, RG, YS; Writing—review & editing: SH, RSB, RG, YS; Funding acquisition: SH and RSB; Resources: RG, AP, AMZ, RAF, and TP; Project administration: SH and RSB; Supervision: SH and RSB.

Corresponding authors

Correspondence to Yuanbin Song or Stephanie Halene.

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Competing interests

Zeidan: AMZ received research funding from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, Amgen, and ADC Therapeutics. AMZ participated in advisory boards, had a consultancy with, and/or received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Trovagene/Cardiff Oncology, Takeda, Ionis, Amgen, Tyme, Aprea, Kura, Janssen, Gilead, and Epizyme. AMZ received travel support for meetings from Pfizer, Novartis, and Trovagene. Flavell: RAF is an advisor to Glaxo Smith Kline, Zai labs and Ventus Therapeutics. Prebet: Boehringer Ingelheim: Research Funding; Novartis: Honoraria; Pfizer: Honoraria; Agios: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Genentech: Consultancy; Tetraphase: Consultancy; Bristol-Myers Squibb: Honoraria, Research Funding. Bindra: Cybrexa Therapeutics: Consultancy, Equity Ownership. Athena Therapeutics: Equity Ownership. Halene: FORMA Therapeutics: Consultancy.

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Gbyli, R., Song, Y., Liu, W. et al. In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2. Leukemia 36, 1313–1323 (2022). https://doi.org/10.1038/s41375-022-01536-x

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